1. Field of Invention
The present invention relates to a bifunctional compound and a manufacturing method thereof, especially to a bifunctional compound containing an amino group and diaminedithiol ligand and a manufacturing method thereof.
2. Description of Related Art
Receptors on human cells are activated by certain kinds of specific compounds such as amines, amino acids, peptides or proteins. By means of such character, these bioactive compounds are labeled with radioactive nuclides. Once entering human bodies, these compounds will crowd toward specific organs or tissues so as to be applied to imaging diagnosis or disease treatment. For example, apoptosis is highly correlated with treatment of a plurality of diseases so that studies regarding radioactive labeled protein Annexin-V have received significant attention.
For direct labeling of proteins or peptides with radiometal isotopes such as Tc-99m, the two parts are tethered by means of a bifunctional ligand. S-Hynic (succinimidyl 6-hydrazinonicotinate hydrochloride) contains an active carboxylic ester that combines with proteins or peptides to generate a strong amide bond. Moreover, it includes pyridinyl and hydrazo groups that react with Tc-99m. Thus S-Hynic is a common bifunctional coupling agent. Furthermore, S-Hynic solution is light sensitive and light causes it to degrade. In addition, S-Hynic itself is unable to form sufficient bonds so that tricine is used as a coligand. Thus there is a need to find out a bifunctional compound (chelating agent) that is with stable physical properties and easy to use.
DADT (diamide dithiol) and BAT (bis-aminoethanethiol) are frequently used organic ligands that bind with technetium (Tc) or rhenium (Re) to form complexes (coordination compounds). As shown in FIG. 1, the representative structure of DADT as well as BAT and their complex reactions with Tc or Re are illustrated. While reacting with MO3+(M=Tc or Re), four protons are released from two amide groups and two thiol groups of DADT. Thus the DADT complex is an anion. When BAT reacts with MO3+(M=Tc or Re), only three protons are released and the complex is electrically neutral.
The thiol group is easily oxidized so that it must be protected. The common protecting groups include COC6H5, CH2C6H4OCH3 and CPh3 etc. Before complex reaction, the protecting group for the thiol group must be removed. For example, COC6H5 is used as a protecting group for the MAG3. Thus the MAG3 is hydrolyzed in alkaline solution so as to remove the protecting group before the complex reaction.
In accordance with above description, a N2S2 ligand having two amide groups and two thiol groups reacts with MO3+(M=Tc or Re) to form a complex anion. Then an amino group is added to this type of ligand so that the ligand reacts with compounds containing carboxylic acids or halogens to form chemical bonds and generate a bifunctional compound. Moreover, CPh3 is used as the protecting group for the thiol group in the present invention. The protecting group (CPh3) is released easily during the complex reaction and there is no need to remove the protecting group in advance. This allows convenient use of the bifunctional compound.